Beta-hydroxyacyl-ACP dehydratase HadAB complex (HadAB) (HadAB)

The Beta-hydroxyacyl-ACP dehydratase HadAB complex is a critical heterodimeric enzyme in Mycobacterium tuberculosis, composed of the HadA (Rv0635) and HadB (Rv0636) subunits (UniProt: P9WNG1, P9WNG3). It functions as a (3R)-hydroxyacyl-acyl carrier protein (ACP) dehydratase within the Fatty Acid Synthase II (FAS-II) system, which is responsible for the elongation of long-chain fatty acids into mycolic acids (PubMed: 19171774). Mycolic acids are essential components of the mycobacterial cell wall, providing a protective barrier against environmental stress and antibiotics (PubMed: 22461519). By catalyzing the dehydration of (3R)-hydroxyacyl-ACP to trans-2-enoyl-ACP, HadAB plays a vital role in maintaining cell wall integrity and bacterial viability. This complex is a validated drug target, as its inhibition leads to the disruption of mycolic acid synthesis and subsequent bacterial death. Several antitubercular agents, including the prodrugs Isoxyl and Thiacetazone, as well as certain flavonoids like butein, have been shown to target the HadAB complex (PubMed: 12485948, 22461519). Inhibition of HadAB results in the accumulation of beta-hydroxy fatty acids and a deficiency in mature mycolic acids, ultimately compromising the structural integrity of the bacterial cell envelope. Understanding the structural and functional aspects of HadAB is crucial for the development of new therapeutics to combat multi-drug resistant tuberculosis.

Other names

HadA-HadB complexRv0635-Rv0636 complex(3R)-hydroxyacyl-ACP dehydratase HadABBeta-hydroxyacyl-acyl carrier protein dehydratase HadAB

Inhibition of the dehydration of (3R)-hydroxyacyl-ACP to trans-2-enoyl-ACP in the Fatty Acid Synthase II (FAS-II) pathway, preventing mycolic acid synthesis.